Mammalian cells sense virus infection by detection of viral nucleic acids. Several sensor pathways of the innate immune system specialize in detection of viral RNA and DNA to induce antiviral type I-interferon (IFN) responses. These responses are essential to control virus infection and prevent e.g. severe courses of SARS-CoV2 infection. Uncontrolled activity of this arm of the immune system, however, can cause massive damage to host tissues, a principle dubbed ‘autoinflammation’. Inappropriate chronic activation of innate antiviral immunity can also result in a break-down of self-tolerance in the adaptive immune system and constitutes a major cause of autoimmunity in Systemic Lupus (SLE) and related conditions.

We focus on molecular mechanisms of chronic activation of the cGAS/STING pathway that senses DNA in the cytosol. As the sensor cGAS does not discriminate between endogenous and microbial DNA, pathogenic activation can result from failure to keep the cytosol free of endogenous DNA. This is a situation that can ensue from defects of cytosolic DNA waste disposal which is primarily a function of the cytosolic DNase TREX1. We address nature and source of TREX1 DNA substrates, the regulation of the immune response in TREX1-deficient cells, and how the lack of TREX1 leads to autoimmunity.

While inherited defects of TREX1 result in fatal disease, we also explore whether cGAS/STING activation by temporary and partial pharmacologic inhibition of TREX1 can be leveraged to invigorate anti-tumor immunity. Impact of STING responses on T cell immunity can enhance, but also compromise T cell responses, depending on intensity and context. Our results in preclinical models indicate that STING activation through induced loss of TREX1 in the adult massively improves T cell-mediated tumor control and synergizes with immune checkpoint inhibition, but does not trigger rapid onset of autoimmunity. We investigate the impact of TREX1 inactivation on DC function and T cell exhaustion.

Funding

DFG: TRR SFB 237 ‚Nucleic Acid Immunity’, Project B17: Molecular and cellular dynamics of nucleic acid-driven immune responses and immunopathology

German Cancer Aid: Project 70116421 Induction of anti-tumor immunity by systemic low-level cGAS/STING signaling

Mast cells are tissue resident hematopoietic cells. They are best known for their pathogenic functions as the major effector cells of allergic, IgE-mediated immune responses. Physiological mast cell functions are less clear and much debate. Mast cell activation can occur through innate immune sensors and other surface receptors, but they are also innate effector cells of humoral adaptive immunity equipped with polyclonal IgE antigen receptors, which they acquire from the circulation by means of their high affinity Fce receptor. Their IgE enables mast cells to sensitively and rapidly respond to antigen. Upon activation, they release the content of their secretory granules that contain histamine and other proinflammatory mediators, as well as large amounts of proteases. Degranulation occurs within seconds to minutes after crosslinking of IgE by antigen. This ultra-fast response protects against environmental hazards, e.g. by proteolytic degradation of animal venoms, expulsion of inhaled toxins from the airways and avoidance behaviour preventing intake of harmful food. However, these mast cell functions are also responsible for key manifestations of allergic diseases. Factors determining whether a MC response is protective or rather results in life-threatening allergy are subject to discussion.

We have generated tools allowing study of mast cell in vivo functions, including transgenic mice expressing Cre-recombinase in mast cells, mast cell reporters and mast cell-deficiency models. We search for novel mast cell functions and currently focus on a subset of mast cells intimately associated with blood vessels that we found are capable of sampling blood vessel content and may provide alarm signals or protection upon detection of circulating hazards.

Principles of activation of type 2 immunity

Allergies, asthma and atopic dermatitis are summarized as ‘atopic diseases’, share a common genetic predisposition, but are also driven by environmental factors. Atopy is associated with deregulated type 2 immunity and overproduction of IgE. We are interested in mechanisms driving pathogenic type 2 responses.

Funding
DFG project RO 2133/12-1 Immunosurveillance of the blood stream by mast cells: Protection against circulating microorganisms, microbial toxins and animal venoms?

DFG: TRR SFB 156 ‚The Skin as Sensor and Effector Organ Orchestrating Local and Systemic Immune Responses’, Project C11N: Immune cell crosstalk in barrier-defective skin driving systemic atopic disease

DFG: FOR 2599 ‚Tissue Type 2 Immunity‘, Project 8: Control of high-affinity IgE responses to animal venoms by skin innate type 2 immunity

Dr. Emilija Marinkovic, Postdoc
Dr. Lena Krämer, Postdoc & Scientific coordinator
Dr. Minyi Chen, Postdoc
Dr. Michael Persicke, Postdoc
Han Gao, Fellow
Yunchen Wu, Fellow
Kristina Link, PhD student
Zeina Salloum, PhD student

Katariana Bezakova, MD student
Cagil Yetis, MD student

Antje Heidtmann, MTA
Sabine Ulbricht, MTA & Lab manager
Lucius Oppel, HiWi